Cyclodextrins have been used widely in many different types of cosmetic, food and pharmaceutical formulations. Cyclodextrins are cyclic carbohydrates derived from starch. The unmodified (parent) cyclodextrins differ by the number of glucopyranose units joined together in the cylindrical structure. The parent cyclodextrins contain 6, 7, or 8 glucopyranose units and are referred to as α-, β-, and γ-cyclodextrin, respectively. The underivatized α-cyclodextrin and β-cyclodextrin are the most widely used cyclodextrins. Each cyclodextrin subunit has secondary hydroxyl groups at the 2 and 3 positions and a primary hydroxyl group at the 6-position. The cyclodextrins may be pictured as hollow truncated cones with hydrophilic exterior surfaces and hydrophobic interior cavities. In aqueous solutions, these hydrophobic cavities provide a haven for hydrophobic organic compounds that can fit all or part of their structure into these cavities. This process, known as inclusion complexation, may result in increased apparent aqueous solubility and stability for the complexed compound. The complex is stabilized by hydrophobic interactions and does not involve the formation of any covalent bonds.
This dynamic and reversible equilibrium process can be described by Equations 1 and 2, where the amount in the complexed form is a function of the concentrations of the drug and cyclodextrin, and the equilibrium or binding constant, Kb. When cyclodextrin formulations are administered by injection into the blood stream, the complex rapidly dissociates due to the effects of dilution and non-specific binding of the drug to blood and tissue components.
                              Drug          +          Cyclodextrin                ⁢                  ↔                      K            b                          ⁢        Complex                            Equation        ⁢                                  ⁢        1                                          K          b                =                              ⌊            Complex            ⌋                                              [              Drug              ]                        ⁡                          [              Cyclodextrin              ]                                                          Equation        ⁢                                  ⁢        2            
Binding constants of cyclodextrin and an active agent can be determined by the equilibrium solubility technique as well as other suitable techniques (T. Higuchi et al. in “Advances in Analytical Chemistry and Instrumentation Vol. 4”; C. N. Reilly ed.; John Wiley & Sons, Inc, 1965, pp. 117-212). Generally, the higher the concentration of cyclodextrin, the more the equilibrium process of Equations 1 and 2 is shifted to the formation of more complex, meaning that the concentration of free active agent is generally decreased by increasing the concentration of cyclodextrin in solution.
α-CD and β-CD are known to be unsafe due to severe nephrotoxicity attributed to their damaging of renal epithelial cells. The mechanism of this renal toxicity is not fully understood. The parent CDs also cause red blood cells hemolysis and membrane irritation that appear to be correlated to their capacity to extract lipid membrane components. A good correlation between the ability of CDs to cause red blood cell hemolysys and their renal toxicity has been noted.
Hydrophobic, hydrophilic, polymerized, ionized, non-ionized and many other modifications of cyclodextrins have been developed, and their use in various industries has been established. Chemical modification of the parent cyclodextrins at one or more of the hydroxyl groups has resulted in derivatives with improved properties. Of the numerous derivatized cyclodextrins prepared to date, only two appear to be commercially viable for pharmaceutical usage: the 2-hydroxypropyl derivatives (HP-CD; neutral cyclodextrins being commercially developed by Janssen and others), and the sulfoalkyl ether derivatives (SAE-CD's, such as sulfobutyl ether, (SBE-CD; anionic cyclodextrins being developed by CyDex, Inc.) However, the HP-β-CD still possesses safety issues that the SBE-CD does not.
A number of references disclose water soluble sulfoalkyl ether cyclodextrins and methods for their preparation and use. An SAE-CD can be made according to the disclosures of Stella et al., Parmerter et al., Lammers et al. or Qu et al. (See citations below).
A sulfobutyl ether derivative of beta cyclodextrin (SBE-β-CD), in particular the derivative with an average of about 7 substituents per cyclodextrin molecule, has been commercialized by CyDex, Inc. as CAPTISOL®. The anionic sulfobutyl ether substituent dramatically improves the aqueous solubility and safety of the parent cyclodextrin. Reversible, non-covalent, complexation of drugs with CAPTISOL® cyclodextrin generally allows for increased solubility and, in some cases, increased stability of drugs in aqueous solutions.

Sulfoalkyl ether cyclodextrins (SAE-CD's), however, are known to have limitations concerning the molecules they can bind with. For example, SAE-CD's but especially Captisol® are known to bind compounds such as nifedipine, nimodipine, nitrendipine and clotrimazole poorly.
Various embodiments of a mixed sulfoalkyl ether cyclodextrin, i.e. a single cyclodextrin comprising two structurally different ether functional groups, are known. Some of the mixed ether cyclodextrins include eicosa-O-(methyl)-6G-O-(4-sulfobutyl)-β-cyclodextrin, heptakis-O-(sulfomethyl)-tetradecakis-O-(3-sulfopropyl)-β-cyclodextrin, heptakis-O-[(1,1-dimethylethyl)dimethylsilyl]-tetradecakis-O-(3-sulfopropyl)-β-cyclodextrin, heptakis-O-(sulfomethyl)-tetradecakis-O-(3-sulfopropyl)-β-cyclodextrin, and heptakis-O-[(1,1-dimethylethyl)dimethylsilyl]-tetradecakis-O-(sulfomethyl)-β-cyclodextrin.
Other known ether cyclodextrin derivatives containing a sulfoalkyl moiety include sulfoalkylthio and sulfoalkylthioalkyl ether derivatives such as octakis-(S-sulfopropyl)-octathio-γ-cyclodextrin, octakis-O-[3-[(2-sulfoethyl)thio]propyl]-β-cyclodextrin], and octakis-S-(2-sulfoethyl)-octathio-γ-cyclodextrin.
Japanese Patent No. JP 05001102 to Yoshinaga discloses a method of preparing sulfonic acid derivatives of cyclodextrins wherein the primary hydroxyl groups of the cyclodextrin are predominantly derivatized to form mono-, di-, tetra-, and hepta-sulfonic acid derivatized CD's.
U.S. Pat. No. 5,241,059 to Yoshinaga discloses methods of preparing cyclodextrins derivatives containing sulfoalkyl ether (SAE), ammonium, phosphoric, carboxyl, hydroxyl, tosyl, t-butyl-dimethylsilyl (TBDMS), azide, trimethyl ammonium, or carboxyalkyl ether CD's. In particular, they disclose mixed derivatives comprising SAE and TBDMS.
PCT International Publication No. WO 01/40316 to Zhang et al. discloses the preparation of 6-mercapto-cyclodextrin derivatives of the general formula CD-6-O—CH2—S—R—X, wherein R can be an alkylene group and X can be an —SO3H group. The cyclodextrin can be α, β, or γ.
Adam et al. (J. Med. Chem. (2002), 45, 1806-1816) disclose a group of CD derivatives containing different functional groups at the C6 position. In particular, they disclose sulfoalkyl (sulfomethyl, sulfoethyl, sulfopropyl) thio ether cyclodextrin derivatives.
Tarver et al. (Bioorganic & Medicinal Chemistry (2002), 10, 1819-1827) disclose sulfoalkyl (sulfoethyl) thioalkyl ether cyclodextrin derivatives wherein derivatization occurs on the C6 position.
U.S. Pat. No. 5,594,125 (Jan. 14, 1997) to Seyschab et al. discloses water soluble cyclodextrin derivatives having at least one lipophilic substituent and one hydrophilic radical per cyclodextrin molecule. The hydrophilic substituent can be methyl, ethyl, hydroxyethyl, hydroxy-i-propyl, hydroxy-n-propyl, dihydroxy-i-propyl, dihydroxy-n-propyl, carboxymethyl, carboxyethyl, carboxy-i-propyl, carboxy-n-propyl or an alkali metal salt of the carboxyalkyl substituents. Particularly preferred embodiments for hydrophilic substituent include methyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, Na-carboxymethyl, K-carboxymethyl or Li-carboxymethyl. The lipophilic substituent can be C5-C12 hydroxy-alkyl, C6-C10 hydroxycycloalkyl, or hydroxypropyl, which is substituted by C4-C12 alkyloxy and/or C6-C10 aryloxy and/or C7-C15 aralkyloxy radicals, where the alkyl radicals can be unbranched or branched. Particularly preferred embodiments for the lipophilic substituent include hydroxyhexyl, hydroxyoctyl, hydroxydecyl, hydroxycyclohexyl, hydroxycyclooctyl, 3-butoxy-hydroxypropyl, 3-hexyloxyhydroxypropyl, 3-(2-ethylhexyloxy)-hydroxypropyl, 3-octyloxy-hydroxypropyl, 3-phenyloxy-hydroxypropyl, 3-cresyloxy-hydroxypropyl or 3-naphthyloxy-hydroxypropyl, where the alkyl radicals are unbranched and even-numbered.
U.S. Pat. No. 5,760,015 (Jun. 2, 1998) and U.S. Pat. No. 5,846,954 to Joullie et al. disclose “one-sided” water soluble cyclodextrin derivatives having at least 10 anionic groups on one side of the CD molecule. The majority of the anionic substituents are located at the C-2 and C-3 positions of the carbohydrate rings of the cyclodextrin. The anionic substituent is the anion of “any strong acid, non-limiting examples of these anions include sulfate, nitrate, sulfonate, and phosphate. Sulfate is preferred.” Several anionic substituents are listed; however, only the sulfate anion is exemplified. The derivative also includes a hydrophobic substituent located at least at the C-6 position of the carbohydrate. None of these patents includes enablement of a polymeric or non-polymeric SAE-AE-CD derivative.
U.S. Pat. No. 5,019,562 to Folkman et al. discloses anionic CD derivatives having a sulfate, phosphate, or carboxylate group. U.S. Pat. No. 5,183,809 to Weisz et al. discloses polyionic derivatives having a sulfate, phosphate, carboxylate or nitrate group. None of these patents includes enablement of a polymeric or non-polymeric SAE-AE-CD derivative.
U.S. Pat. No. 5,658,894 to Weisz et al. suggest polymeric CD derivatives, wherein the CD comprises anionic R groups selected from the group consisting of sulfate, phosphate, sulfonate, carboxylate and nitrate, and nonanionic R groups selected from the group consisting of H, alkyl, aryl, ester, ether, thioester, thioether. This patent includes no enablement of a polymeric or non-polymeric SAE-AE-CD derivative.
Alkyl ether derivatized cyclodextrins (AE-CD's) are known. They have been described in various patent literature and their synthesis and properties have been well documented in various reviews and books (see Fromming and Szejtli, Cyclodextrins in Pharmacy, Kluwer Academic Publishing, Dordrecht, 1994 and references therein). Methyl ether CDs are presumed to be strong binders by raising the “height” of the CD ring thus providing an additional area for interaction with interacting molecules. However, a key limitation of these derivatives is their water solubility. In particular, higher alkylated CDs such as ethyl and propyl ether CDs have shown decreasing water solubility with the increasing TDS (total degree of substitution).
As noted above with regard to the SAE-CD's, AE-CD's are also known to have limited utility due to their poor solubility, and lack of safety. For example, AE-CD's are also known to cause a significant amount of red blood cell hemolysis when administered to a subject. Red blood cell hemolysis has been correlated with increased renal toxicity and membrane disruption. AE-CD's, however, can solubilize some compounds better than SAE-CD's can.
To the knowledge of the present inventors, a mixed ether cyclodextrin comprising an alkyl ether functional group and a sulfoalkyl ether functional group on the same cyclodextrin has only been disclosed once. Jiczinszky et al. (“Cyclodextrin: From Basic Research to Market”, International Cyclodextrin Symposium, 10th, Ann Arbor, Mich., United States, May 21-24, 2000 (2000), 46-52; Wacker Biochem Corp.: Adrian, Mich.) disclose a proposed synthesis of a permethylated 6-O-sulfobutyl ether cyclodextrin derivative. In particular, they disclose a 6-O-(4-sulfobutyl)-permethylated-β-cyclodextrin derivative, wherein the derivative contains only a single sulfobutyl moiety. However, in communications with the author, it was confirmed that the proposed synthesis could not be used to prepare the target derivative. This cyclodextrin derivative, therefore, likely possesses properties that are very similar to the permethylated-β-cyclodextrin, and as has been noted herein, alkylated cyclodextrin derivatives are known to cause a significant amount of hemolysis when administered to a subject. Earlier work by Rajewski et al (Journal of Pharmaceutical Sciences, (1995), 84, 927-932) showed that low degrees of sulfobutylation did not prevent red blood cell hemolysis and that higher degrees of substitution were preferable.
It is known in the art that the method of preparation of a cyclodextrin derivative can have a significant impact upon final structure and associated properties of a product derivative. The synthetic scheme can alter the total degree of substitution (TDS) as well as the regiochemistry of substitution (the substitution pattern). For example, the interaction of an alkylating agent with a CD during alkylation, changing of the pH of the reaction milieu, and/or varying of the molar ratio of alkylating agent to CD during alkylation can affect the TDS and the substitution pattern.
A need remains for an improved SAE-CD as well as an improved AE-CD, since each of those derivatives is known to have limitations. Modern drug discovery processes are identifying larger more complex molecules whose physical and chemical properties, especially solubility and stability are becoming more problematic. Therefore, there is a need for CDs capable of interacting with larger more complex molecules. AE-CDs of both β- and γ-CDs can provide this increased area for interaction but suffer from severe safety issues. It would be extremely beneficial to identify a cyclodextrin derivative that is able to provide enhanced properties over a structurally related SAE-CD and over an AE-CD. It would be useful to identify a CD derivative having the beneficial properties of an SAE-CD and an AE-CD but having less of the disadvantages typically associated with those derivatives.